Abstract The ocular surface system uses innate- and adaptive mucosal immune mechanisms to prevent infection and, thereby, decrease the risk of inflammatory damage to the cornea. As effectors of mucosal immunity, the lacrimal gland (LG) epithelia deliver both sIgA and inflammatory effector molecules into the ocular surface fluid. They also secrete paracrine mediators, which establish the stroma as a specialized niche for differentiation and survival of IgA+-secreting plasmablasts. A by-product of the sIgA delivery mechanism is the release of autoantigens. Certain paracrine mediators tend to enforce tolerance to the autoantigens, while others are potentially pro-inflammatory. Failure of this network of counterpoises becomes manifest clinically as the dry eye syndrome. That dry eye occurs more frequently among women indicates that systemic hormones exert critical influences, and there is long-standing evidence that they do so by controlling the LG epithelia's expression of paracrine mediators. The investigators'interdisciplinary team recently found that elevated estradiol (E2), progesterone (PRG) and prolactin (PRL) induce profound cellular physiological- and immunoarchitectural transformations;E2 and PRG alter the spatially-organized expression of paracrine mediators, while PRL both changes the expression of certain mediators and also diverts increased protein secretory traffic from the exocrine pathway to the paracrine pathway. These findings provide paradigms for endocrinological states that cause the system to initiate inflammatory processes and for states that cause previously tolerable environmental stresses to provoke inflammatory processes, which become self- perpetuating. Specific Aim 1 addresses questions concerning E2- and PRG-mediated support for, and suppression of, the regulatory mediators, TGF-[unreadable] and IL-10, and the potentially inflammatory mediators, IL-6 and PRL, in epithelial cells of the acini and interlobular ducts. Specific Aim 2 addresses the influences of systemic PRL on local PRL in a setting of low systemic E2, mimicking the post-menopause, a non-suckling puerperium, and lactation, and in a setting of elevated systemic E2 mimicking that of a woman using oral contraceptives. Together, Aims 1 and 2 test the hypothesis that certain endocrinological states allow the system to initiate inflammatory autoimmune responses. Specific Aim 3 tests the hypothesis that certain systemic hormones can support a counterpoise to the tendency of elevated PRL to initiate inflammatory processes. This hypothesis suggests a novel strategy for dry eye therapy. Specific Aim 4 tests the hypothesis that homeostatic states associated with certain endocrine settings cause desiccation or trauma at the ocular surface to elicit exaggerated inflammatory responses